1. Technical Field
This document relates to methods and materials involved in detecting mutations linked to dementia (e.g., frontotemporal dementia) as well as methods and materials involved in detecting reduced progranulin expression. This document also relates to methods and materials involved in treating mammals having or being susceptible to developing neurodegenerative disorders (e.g., frontotemporal dementia). For example, this document relates to methods and materials involved in using a nucleic acid encoding a progranulin polypeptide or an agent that increases progranulin polypeptide levels to treat a mammal (e.g., human) having a neurodegenerative disorder.
2. Background Information
Frontotemporal dementia (FTD) is the second most common cause of dementia in people under 65 years (Clinical and neuropathological criteria for frontotemporal dementia. The Lund and Manchester Groups. J. Neurol. Neurosurg. Psychiatry, 57:416-8 (1994)). A large proportion of FTD patients (35-50%) have a family history of dementia consistent with a strong genetic component to the disease (Chow et al., Arch. Neurol., 56:817-22 (1999); Stevens et al., Neurology, 50:1541-5 (1998); and Mann, Brain Pathol., 8:325-38 (1998)). Mutations in the gene encoding the microtubule associated protein tau (MAPT) were shown to cause familial FTD with Parkinsonism linked to chromosome 17q21 (FTDP-17; Hutton et al., Nature, 393:702-5 (1998)). The neuropathology of patients with defined MAPT mutations is characterized by the presence of cytoplasmic neurofibrillary inclusions composed of hyperphosphorylated tau (Hutton et al., Nature, 393:702-5 (1998) and Ghetti et al., Brain Res. Bull., 50:471-2 (1999)).
In an increasing number of FTD families with significant evidence for linkage to the same region on chromosome 17q21 (D17S1787-D17S806), the disease can not be explained by mutations in MAPT, and patients also consistently lack tau-immunoreactive inclusion pathology (Rademakers et al., Mol. Psychiatry, 7:1064-74 (2002); Rosso et al., Brain, 124:1948-57 (2001); Lendon et al., Neurology, 50:1546-55 (1998); Kertesz et al., Neurology, 54:818-27 (2000); Froelich et al., Am. J. Med. Genet., 74:380-5 (1997); Bird et al., Neurology, 48:949-54 (1997); and Rademakers et al., (ed. Cummings, J. L. e.) 119-139 (Springer-Verlag, Berlin, 2005)). In contrast, tau-negative FTD-17 patients have ubiquitin-immunoreactive (ub-ir) neuronal cytoplasmic inclusions (NCI) and characteristically lentiform ub-ir neuronal intranuclear inclusions (NII; Rademakers et al., (ed. Cummings, J. L. e.) 119-139 (Springer-Verlag, Berlin, 2005)).